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Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor.
[familial hypocalciuric hypercalcemia]
The
Ca
(
2
+
)
-
sensing
receptor
(
CaSR
)
belongs
to
the
class
III
G-
protein-coupled
receptors
(
GPCRs
)
,
which
include
receptors
for
pheromones
,
amino
acids
,
sweeteners
,
and
the
neurotransmitters
glutamate
and
gamma-aminobutyric
acid
(
GABA
)
.
These
receptors
are
characterized
by
a
long
extracellular
amino-terminal
domain
called
a
Venus
flytrap
module
(
VFTM
)
containing
the
ligand
binding
pocket
.
To
elucidate
the
molecular
determinants
implicated
in
Ca
(
2
+
)
recognition
by
the
CaSR
VFTM
,
we
developed
a
homology
model
of
the
human
CaSR
VFTM
from
the
x-
ray
structure
of
the
metabotropic
glutamate
receptor
type
1
(
mGluR
1
)
,
and
a
phylogenetic
analysis
of
14
class
III
GPCR
VFTMs
.
We
identified
critical
amino
acids
delineating
a
Ca
(
2
+
)
binding
pocket
predicted
to
be
adjacent
to
,
but
distinct
from
,
a
cavity
reminiscent
of
the
binding
site
described
for
amino
acids
in
mGluRs
,
GABA-B
receptor
,
and
GPRC
6
a
.
Most
interestingly
,
these
Ca
(
2
+
)
-
contacting
residues
are
well
conserved
within
class
III
GPCR
VFTMs
.
Our
model
was
validated
by
mutational
and
functional
analysis
,
including
the
characterization
of
activating
and
inactivating
mutations
affecting
a
single
amino
acid
,
Glu-
297
,
located
within
the
proposed
Ca
(
2
+
)
binding
pocket
of
the
CaSR
and
associated
with
autosomal
dominant
hypocalcemia
and
familial
hypocalciuric
hypercalcemia
,
respectively
,
genetic
diseases
characterized
by
perturbations
in
Ca
(
2
+
)
homeostasis
.
Altogether
,
these
data
define
a
Ca
(
2
+
)
binding
pocket
within
the
CaSR
VFTM
that
may
be
conserved
in
several
other
class
III
GPCRs
,
thereby
providing
a
molecular
basis
for
extracellular
Ca
(
2
+
)
sensing
by
these
receptors
.
Diseases
Validation
Diseases presenting
"autosomal dominant hypocalcemia"
symptom
familial hypocalciuric hypercalcemia
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